PO.IM02.04 · 免疫学
经突变特征校正的模型揭示HLA介导的非小细胞肺癌（NSCLC）抗原性突变耗竭
Mutational-signature adjusted models reveal HLA-mediated depletion of antigenic mutations in non-small cell lung cancer (NSCLC)
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：量化人类肿瘤中的免疫编辑具有挑战性，因为观察到的突变模式同时反映了突变过程和选择作用。HLA I类基因型是否会一致地影响哪些体细胞突变得以持续存留，目前尚不清楚。
方法：来自CPTAC NSCLC肿瘤及配对血液和邻近正常肺组织的全基因组测序（WGS）数据，采用已建立的流程进行了种系单核苷酸多态性（SNP）、体细胞单核苷酸变异（SNV）、HLA分型、新表位预测和突变特征分解。对SNP/SNV进行了密码子位置、所产生氨基酸及进化相似性指标（BLOSUM62、PAM250、Miyata、Atchley、Grantham）的注释。将四位数HLA等位基因归并为已识别的超型；IC50≤150 nM的新表位被视为高亲和力。使用GRCh38参考序列、突变特征和肿瘤突变负荷构建预期非同义突变的模型，并采用余弦相似度与观察到的SNP/SNV进行比较。采用ANOVA和广义线性模型并进行FDR校正来评估统计学显著性。
结果：成功处理了219例（111例LUAD，108例LUSC）。SNP中位数为862.3，SNV为103.8，每例伴随的预测新表位中位数为62.5（其中高亲和力4.9个）。源自第三密码子位置（N=96）的氨基酸替换比源自位置1和2（N=226）的替换具有更高的相似性（p<0.001）。SBS4在167例（76.3%）肿瘤中占主导；在血液中，SBS5和SBS58分别是152例（69.4%）和55例（25.1%）病例的特征。密码子位置偏倚在不同特征之间存在差异，与SBS5和SBS58相比，SBS4显示出位置3替换的相对耗竭（p<0.001）。基于特征的建模显示余弦相似度>0.90，其中SBS4的余弦相似度高于SBS5和SBS58。氨基酸替换的ANOVA比较揭示，多个超型（A02、B27、B44）存在锚定替换以及携带这些替换的高亲和力新表位的相对耗竭（FDR<0.05）。
结论：种系SNP表现出强烈的进化约束，而体细胞SNV则表现出极小的内在密码子位置偏倚，支持癌症突变发生是随机过程这一假说。控制突变特征后揭示了HLA特异性的免疫编辑，表明抗原性突变在特定HLA背景下被选择性耗竭。这一以特征为条件的框架为改善新抗原预测和免疫肿瘤学转化提供了一个具有临床可操作性的平台。
查看英文原文 English abstract
Background : Quantifying immune editing in human tumors is challenging because observed mutation patterns reflect both mutational processes and selection. Whether HLA class 1 genotypes uniformly influence which somatic mutations persist remains unclear.
Methods : Whole-genome sequencing (WGS) from CPTAC NSCLC tumors with matched blood and adjacent normal lung underwent germline single nucleotide polymorphism (SNP), somatic single nucleotide variant (SNV), HLA typing, neoepitope prediction, and mutational signature decomposition using established pipelines. SNP/SNVs were annotated with codon position, resulting amino acids, and evolutionary similarity metrics (BLOSUM62, PAM250, Miyata, Atchley, Grantham). Four-digit HLA alleles were collapsed into recognized supertypes; neoepitopes with IC50 ≤150 nM were considered high-affinity. Models of expected nonsynonymous mutations were created using the GRCh38 reference, mutational signature, and tumor mutation burden and compared to observed SNP/SNVs using cosine similarity. Statistical significance was assessed using ANOVA and generalized linear models with FDR correction.
Results : 219 cases (111 LUAD, 108 LUSC) were processed successfully. Median SNPs were 862.3, SNVs were 103.8 with an associated median of 62.5 predicted neoepitopes (4.9 high-affinity) per case. Amino acid substitutions arising from the third codon position (N=96) had higher similarity than those from position 1 and 2 (N=226), (p<0.001). SBS4 dominated 167 (76.3%) tumors; in blood, SBS5 and SBS58 characterized 152 (69.4%) and 55 (25.1%) cases, respectively. Codon-position biases differed across signatures, with SBS4 showing relative depletion of position-3 substitutions compared to SBS5 and SBS58 (p<0.001). Signature-based modeling demonstrated cosine similarity >0.90 with higher cosine similarity in SBS4 compared to SBS5 and SBS58. ANOVA comparisons of amino acid substitutions revealed multiple supertypes (A02, B27, B44) with relative depletion of anchor substitutions and high-affinity neoepitopes with these substitutions (FDR<0.05).
Conclusion : Germline SNPs exhibit strong evolutionary constraint, whereas somatic SNVs show minimal intrinsic codon-position bias, supporting the hypothesis that cancer mutagenesis is a random process. Controlling for mutational signature uncovers HLA-specific immune editing, demonstrating that antigenic mutations are selectively depleted in specific HLA contexts. This signature-conditioned framework provides a clinically actionable platform for improving neoantigen prediction and immuno-oncology translation.
利益披露 Disclosure
A. L. Cummings,
Tempus Independent Contractor.
AstraZeneca Independent Contractor.